Studies completed, underway or planned on the target tissue toxicity of the nitrosoureas (e.g., MeCCNU, BCNU, chlorozotocin and streptozotocin) include: a) the development of in vivo models of nephrotoxicity; b) elucidation of the biochemical mechanisms underlying the delayed and progressive nephropathy of MeCCNU; c) characterization and mechanism of the acute nephrotoxicity of streptozotocin. The initial emphasis has been primarily on MeCCNU. We have developed a reliable model of MeCCNU renal damage in BDF mice and Fischer 344 rats and have shown that histopathological changes produced by the drug are closely paralleled by marked changes in biochemical parameters (e.g., PAH transport) measurable in vitro in kidney slices, as well as by certain in vivo renal function tests (e.g., urinary osmolality and excretion of kidney-derived urinary enzymes). Preliminary studies show the Fischer rat to provide a relevant model also for studying the nephrotoxicity of other nitrosoureas. For example, streptozotocin was found to be acutely nephrotoxic, as measured by in vivo renal function tests, whereas, low doses of chlorozotocin result in a chronic progressive nephropathy. The overall goals of these studies are to: a) elucidate the chemico-biologic events that underlie the nephrotoxicity of the nitrosoureas and b) develop improved methods for predicting, monitoring or treating such reactions in patients.